HU196070B - Process for production of new substituated amins containing naphtiridine chain - Google Patents

Abstract

The invention provides new substituted amides of formula: R-CONH-Het in which: either R is cycloalkyl (3 to 6 carbons), cyclohexadienyl, phenyl, substituted phenyl or a heterocyclic systems chosen from 3-pyridyl, alkyloxy-3-pyridyl, thienyl, alkylthienyl, furyl, tetrahydropyridyl, pyridazinyl, and alkylpyridazinyl, and Het is 1,8-naphthyridin-2-yl substituted at the 7-position by alkyloxy, alkylthio or alkylsulphinyl, themselves substituted with alkylamino or dialkylamino (in which the alkyl portions can form, with the nitrogen atom, a 5- or 6-membered heterocyclic system optionally containing another hetero atom chosen from O, S or N, and optionally substituted by alkyl) or by dialkylcarbamoyl or N-alkyl-N-(alkyloxycarbonyl)amino, or substituted at the 7-position by dialkylaminovinyl; or R is 4-(alkylamino)phenyl or 4-(alkyloxycarbonylamino)phenyl and Het is 1,8-naphthyridin-2-yl substituted at the 7-position by alkyloxy or alkylthio, the said alkyl radicals and alkyl portions containing 1 to 4 carbons, their salts, their preparations and pharmaceutical compositions which contain them. These new substituted amides are especially active as anxiolytics, hypnotics, anticonvulsants, antiepileptics and muscle relaxants.

Description

SUMMARY OF THE INVENTION The present invention relates to novel substituted anode derivatives of 2-amino-1,8-naphthyridine and their acid addition salts, and to pharmaceutical compositions containing them.

The active compounds of the present invention are primarily anxiolytic, hypnotic, anticonvulsant, anti-epileptic and muscle laxative.

A 84.00489. It is known from PCT Patent Application Publication No. PCT Publication No. 3,800,600 that the benzamide derivatives of formula (A) are effective for the treatment of irregular heartbeat.

No. 73.05482. Dutch Patent Application No. 3,993,656; U.S. Pat. No. 4,198 discloses 1,8-naphthyridine derivatives of the general formula (B), which can be used peripherally to dilate bronchi and blood vessels and to reduce blood pressure.

The novel substituted amide derivatives of the present invention are of formula (I). In the general formula (I)

R 3 is C 3-6 cycloalkyl, phenyl, one or two fluorine atoms, C 1-4 alkoxy at the 3- or 4-position, or C 1-4 alkylamino at the 4-position or C 1-4 alkyl. phenyl substituted with alkyl) oxycarbonylamino; and

Seven is 1,8-naphthyridyl-2-yl substituted at the 7-position by C 1-4 alkyloxy or C 1-4 alkylthio or C 14 alkylsulfinyl, which are substituted by N, (C 1 -C 4 alkyl) -N- (C 2 -C 5 alkyloxycarbonyl) amino, di (C 1 -C 4 alkyl) carbamoyl, C 1 -C 4 alkyl -amino, or a di (C 1-4 alkyl) amino group whose alkyl moieties are optionally substituted with a C 1-4 alkyl group and optionally substituted with another heteroatom nitrogen or oxygen They may form a 6-membered heterocyclic ring, or may be substituted in the 7-position by a di-C 1-4 alkyl) aminovinyl group, or

R 4 is C 1-4 alkylamino) phenyl or C 2-5 alkoxycarbonylamino o) phenyl, and

There are seven 1,8-naphthyridin-2-yl groups substituted at the 7-position with C 1-4 alkyloxy. . '

In the above groups, the alkyl chains may be straight-cut branched.

According to the present invention, amides of the formula wherein R and Sev are as defined above, with the proviso that Sev may not be 7- [di (C 1 -C 4 alkyl) amino vinyl] -1,8-naphthyridine -2-yl can be prepared by reacting acids or reactive derivatives of the formula R-COOH - R is as defined above - and amines of the formula HjN-Het - Sev is as defined above.

When starting from an acid of formula (II), it is carried out in the presence of a peptide-like condensation such as a carbodiimide such as dicyclohexylcarbodiimide, or Ν, Ν'-carbonyldiimidazole or 2-ethoxy-1 / ethoxy. -carbonyl) -1-2-dihydro-4-dnoline is used in an organic solvent such as ether such as tetrahydrofuran, dioxane, glim, diglyme, amide such as dimethylformamide, ntril such as acetonitrile, or chlorinated solvent such as methylene chloride or dichloroethane. in chloroform at -0 ° C to the reflux temperature of the mixture, preferably at 20 ° C.

In the case of starting from a reactive derivative of an acid of formula II, an anhydride, mixed anhydride, acid halide or an ester, which may be selected from the activated or non-activated esters of the acids of formula II, may be reacted. Thus, it is possible to work in an organic medium, optionally an acid scavenger such as an organic nitrogenous base such as trialkylamine, pyridine derivative, 1,8-diazabicyclo [5.4.0] undec-7-ene or diaza-15-bicyclo [4.3.0 in the presence of non-5-ene in one of the above solvents or a mixture of the above solvents at a temperature between 0 ° C and the reflux temperature of the reaction mixture. However, it is also possible to work in a two-phase medium comprising water and organic material in the presence of an alkali metal hydroxide or alkaline earth metal hydroxide, e.g. sodium hydroxide or potassium hydroxide, or an alkali metal carbonate or bicarbonate in the presence of kaonate or bicarbonate at a temperature of 0 ° C to 40 ° C. Alternatively, the reaction mixture may be worked at the melting point of the reaction mixture without the use of a solvent.

It is also to be understood that when an acid of formula (II) (or a reactive derivative thereof) or an amine of formula (III) is substituted with a secondary amino group, this group must be protected beforehand by a - commonly used to protect amines - leaving the rest of the molecule intact.

All easily removable groups conventionally used in peptide chemistry may be used for protection, such as trifluoroacetyl, tertiary-butoxycarbonyl-tube port, trichloro-2,2-2-e-ethoxycarbonyl, trityl, benzyl. a benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group or a formyl group.

In the case where there are multiple protecting groups on the molecule, removal of these groups can be accomplished simultaneously or sequentially.

For example:

in the presence of tert-butoxycarbonyl, trityl, p-methoxybenzyloxycarbonyl or formyl, the removal of these protecting groups can be accomplished in an acidic medium. It is preferable to use trifluoroacetic acid at a temperature of 0 ° C to 30 ° C or anhydrous formic acid or aqueous formic acid, para-toluenesulfonic acid or methanesulfonic acid in acetonitrile at a temperature between 20 ° C and reflux temperature, »

in the case of the trifluoroacetyl protecting group, the removal may be carried out in an alkaline medium. For example, we use an alkali metal carbonate in a medium containing water and alcohol,

-2. 1

- when the 2,2,2-trichloroethoxycarbonyl group or the p-nitrobenzyloxycarbonyl group is the protecting group to be removed, the removal is effected by reduction, for example with zinc in an acidic medium,

in the case where the benzyl group or the benzyloxycarbonyl group is the protecting group, the removal is effected by catalytic hydrogenation.

The present invention provides compounds of formula (I) wherein R is as previously defined and Seven is a Cyano-7-alkylsulfinyl-13-naphthyridine-241 group which may be substituted by groups as defined in formula (I). can also be prepared by oxidation of the corresponding compounds of formula I wherein R is as defined above and Sev is a 7-alkylthio-1,8-naphthyridine-241 group, which is substituted as given when interpreting general formula (I).

The reaction is usually carried out in the presence of an oxidizing agent, by any method commonly used to oxidize sulfides to sulfoxides, which leaves other parts of the molecule intact. Of the known oxidizing agents, hydrogen peroxide, inorganic or organic peracids such as pionic acid or 3-chloroperbenzoic acid are preferred.

Preferably, the reaction is carried out in a chlorinated solvent such as methylene chloride or chloroform at a temperature of -0 ° C to 40 ° C.

It is understood that in the case where there is a secondary amino group of a compound of the formula I wherein Sev is a 7- (alkylthio) -1,8-naphthyridin-2-yl group, this compound it must be put in a protected state at the start of the procedure. Thus, the oxidation of the protecting groups occurs after the oxidation reaction in any of the methods used, which leaves the rest of the molecule unchanged.

According to the present invention, amides wherein R is as defined above and Sev is a 7- (dialkylamino-vinyl) -1,8-naphthyridin-2-yl group, ÖV) and (V) can be prepared by reacting compounds of the general formula (I). The BELT) wherein R represents an alkyl group and R _2, R ₃ and R 4 are independently alkoxy radical or a dialkylamino group. In formula (V), R is as defined herein.

It is typically carried out in an organic solvent such as an amide - for example, dimethylformamide, dimethylacetamide tami db n, hexamethylphosphoric triamide - or nitrile - such as acetonitrile - _á or these mixed solvent, at a temperature between 20 ^Ti C to 150 ° C .

In the case where a reactive compound is used wherein R ₃ and / or R 4 in the formula (IV) represents a dialdylamino group, this group should be such that the corresponding amine is more volatile than HNR, Ri.

The acids of formula (II) may be prepared by the methods set forth in the following Examples, or by the methods listed below, or by analogy to these methods:

- H.D. Hartough: The Chemistry of Heterocyclic Compounds, Thiophene and Its Derivatives, Interscience Publishers Inc., New York, 1952,363. d.

- J. W. Mason: The Chemistry of Heterocyclic Compounds, Pyridazine Carboxylic Acids, John Wiley and Sons Inc., New York, 1973,407. 0,

- Ε. P. Oil, The Chemistry of Heterocyclic Compounds, Pyridinecarboxylic Acids, Interscience Publishers Inc., 1962,179. She.,

A. A. Petrov et al. Obshej. Kim, 26.1588 (1956),

S Hunig et al., Chem. Bér. 90, 238 (1957) (for cyclohexadienylcarboxylic acids).

Amines in which the alkyl in the formula (III) is optionally substituted by an alkylamino group, a dialkylamino group, an N-alkH-N-alkyloxaminocarbonyl group or a dialkylcarbamoyl group an oxy or alkylthio group (in which the alkyl moieties, together with the nitrogen atom to which they are attached, may form a heterocyclic group, e.g., as previously defined), may be prepared from the corresponding amine having the formula: is a 1,8-naphthyridin-2-yl substituted with a halogen atom - this halogen atom is preferably chlorine. The preparation is carried out by reacting the amine (VIa) with thiols of formula ^v brain (VIb), compounds containing hydroxyl groups of formula. In the formulas (VIa) and (VIb), R 'is an alkyl group which may be optionally substituted with substituents as previously stated. The starting materials are reacted in an alkaline medium with the appropriate alcoholate or thiolate,

The reaction is usually a strong base such as sodium hydroxide, potassium hydroxide, quaternary ammonium hydroxide, sodium ethylate and the like. - going to the presence of a terminal temperature of 50 ^& C and 50 ° C, or the corresponding alcoholate or thiolate - e.g. sodium alcoholate - the presence of a solvent such as an amide - as dimethylformamide ether - such as tetrahydrofuran or dimethoxyethane - chlorinated solvent For example chlorobenzene, or an oxide such as dimethyl sulfoxide, or in the absence of a solvent, in the presence of an excess of a hydroxyl or mercapto compound at a temperature between 70 ° C and the reflux temperature of the reaction mixture. Optionally, the reaction is carried out in the presence of a phase transfer catalyst such as tris (dioxa-5,6-heptyl) aniline or benzyltriethylammonium chloride.

When an alcoholate or thiolate is used, these compounds are prepared in advance: from alcohol (VIa) with sodium or from VIb (sodium) at temperatures between 20 and 80 ° C, and with sodium hydride (0 ° C and 20 ° C). At a temperature in the range of C, in a solvent such as dimethylformamide, dimethoxyethane or tetrahydrofuran. The alcoholate thus obtained need not be isolated to be used in the next reaction.

Λ Het-NHí - Seven at position 7 represents a 1,8-naphthyridine-241 group substituted by a halogen atom - can be prepared as described by S. Carboni (Gazz. Chim. Italiana, 96, 1456 (1966)). . '

Amines of which in formula (H1) Sev is an alkylsulfinyl group substituted with the substituents given above may be prepared by oxidation of the corresponding amines having the formula (Seven) in which formula (7) is substituted. represents an alkylthio group,

The reaction proceeds in a similar manner, i.e. under similar conditions, to those described for the preparation of the amides of which in formula (I) is Seven-substituted alkylsulfinyl, starting from the amides of formula (I) in which seven are substituted. represents an alkylthio group.

Optionally, it is convenient to protect the amino group prior to the reaction. In this case, any suitable protecting group may be introduced into the molecule which, upon removal, will not alter the structure of the rest of the molecule and will behave in an inoxic manner. Suitable protecting groups are, for example, chloroacetamido or phthalimido.

Compounds of formula IV can be prepared according to the methods of H. Bredeck et al., Chem. Bér., 101.41, (1968) and Angew. Chem. Interhat. Ed., 2,738 (1963).

Compounds of formula (V) may be prepared in a similar manner to compounds of the present invention from an acid of formula (II) or a reactive derivative of this acid, 2-amino-7-methyl-1,8-naphthyridine.

2-Amino-7-methyl-1,8-naphthyridine was synthesized from Ε. V. Brown, J. Org. Chem. 30.1607 (1965).

The new amides of the present invention may optionally be converted into acid addition salts with acids.

Pharmaceutically acceptable salts include the addition salts of mineral acids, such as hydrochlorides, hydrobromides, sulfates, nitrates and phosphates, or organic acid addition salts (e.g., succinates, fumarates, maleate and p-salts). ).

The new amides obtained by the process of the present invention may optionally be purified by physical methods such as crystallization and chromatography.

The compounds of formula (I) obtained by the process of the present invention have pharmacologically interesting properties, such as anxiolytic, hypnotic, anticonvulsant, antiepileptic and muscle relaxant activity, as demonstrated by the following examples.

Specifically, they exhibit good affinity for benzodiazepine receptor sites at concentrations of 10 nM to about 1000 nM, as determined by the method described by J.C. Blanchard and L. Julou (J. of Neurochemistry, 40. 601 (1983)) in Squires and Based on the work of Braestrup (Natúré, 266,732 (1977)).

In accordance with the method of Everett and Richards (J. Pharmacol., 81, 402 (1944)), the compounds of the present invention were found to be effective in the control of pentetrazole in animals (mice) at doses of 10 and 200 mg / kg orally

Otherwise, the compounds of the present invention have low toxicity: their DL _J0 values for oral administration in mice range from 300 mg / kg to greater than 900 mg / kg.

Of particular interest are compounds of the present invention which have the following general formula (I):

a) - R is phenyl or phenyl substituted at the 4-position by 1 or 2 fluoro atoms, an alkyloxy group, an amino group or an alkyloxycarbonylamino group, and - Seven are 1,8-naphthyridine Represents a -2-yl group substituted in the 7-position with an alkyloxy group, an alkylthio group, a dialkylaminovinyl group or an alkylsulfinyl group which itself is substituted with an N-alld1-N-alkyloxycarbonylamino group or a dialkylamino group whose alkyl moieties, taken together with the nitrogen atom to which they are attached, may form a six membered heterocyclic ring the ring may optionally contain oxygen or nitrogen as an additional heteroatom and may be optionally substituted with an alkyl group or

b) - R is 4- (alkylamino) phenyl or 4- (allyloxy) carbonylamino, and

- Seven 1,8-naphthyridin-2-yl groups substituted in the 7-position by an alkyloxy group.

(The alkyl groups and alkyl moieties mentioned above may be linear or branched and have from 1 to 4 carbon atoms.)

Particularly active compounds include those having the formula (I):

- R is phenyl substituted with one or two fluorine atoms or with an alkyloxy group in the 4-position, and

- Seven 1,8-naphthyridin-2-yl groups substituted in the 7-position by a C2-C3 alkyloxy group or a C2-C3 alkylthio group which are themselves they are substituted with a dialkylamino group whose alkyl moieties have from 1 to 2 carbon atoms.

Examples of such compounds are:

- N- [7- [3- (dimethylamino) propoxy] -1,8-naphthyridine-241] -4-methoxybenzamide,

- N- [7- [3- (dimethylamino) propoxy] -1,8-naphthyridin-2-yl] -4-methoxybenzamide,

- N- [7- / 2-dimethylamino-ethyl-thio-1,8-naphthyridin-2-yl] -4-methoxy-benzamide,

- N- [7- (3- (dimethylamino) propylthio) -1,8-naphthyridin-2-yl] 4-methoxybenzamide,

- N- [773- (dimethylamino) propoxy] -1,8-naphthyridin-2-yl] -2,6-difluorobenzamide.

The following examples illustrate the process of the present invention.

Example 1

2000 cm ³ of anhydrous tetrahydrofuran reconstituted k0 / 2 g of 4-methoxy-benzoic acid was added 10.9 g of Ν, Ν'-carbonyldiimidazole. Immediately gas-41 development was observed. The mixture is stirred for two hours at a temperature in the region of 20 L until gas evolution is complete. The mixture is then added

11.6 g of 2-amino-7- [2- (dimethylamino) ethoxy] -1,8-naphthyridine are added and the mixture is refluxed for 25 hours. The mixture was then poured into 1200 cm ^{3 of} distilled water and the precipitate was filtered off, washed with water, air dried and dried under reduced pressure at 0.07 kPa to 30 ° C.

3 g of a solid which was dissolved in 50 cm ³ of boiling ethanol. After cooling for 15 hours at 4 ° C, the crystallized material is filtered off, washed twice with 10 cm ^{3 of} ethanol and dried at 20 ° C under reduced pressure (0.07 kPa). 4.5 g of N- [7- (2-dimethylamino) ethoxy] -1,8-naphthyridin-2-yl] -4-methoxybenzamide are obtained, m.p. 77-80 ° C.

2-Amino-7- [2- (dimethylamino) ethoxy] -1,8-naphthyridine can be prepared as follows:

A mixture of 89.7 g of 2-amino-7-chloro-1,8-naphthyridine, 178 g of 2-dimethylaminoethanol and 65.8 g of pelletized solution is kept at 120 ° C for two and a half hours. , Consisting of 85% potassium hydroxide. The mixture was poured into 1500 cm ^{3 of} distilled water and the precipitated material was removed by filtration.

The filtrate was extracted three times with 300 cm <^{3> of} methylene chloride. The organic extracts were washed twice with 200 cm ^{3 of} distilled water, dried over magnesium sulfate and evaporated to dryness at 60 ° C under reduced pressure (4 kPa).

The product thus obtained is suspended in 150 cm ^{3 of} isopropyl oxide. The suspension was stirred for one hour, the insoluble material was filtered off, washed with 25 cm <^{3> of} isopropyl oxide and dried at 20 [deg.] C. under reduced pressure (0.07 kPa). This gives 45.8 g of 2-amino-7- [2- (dimethylamino) ethoxy] -1,8-naphthyridine, m.p. 105 ° C.

Example 2

Proceed as described in Example 1, except that 10 g of 4-methoxybenzoic acid,

Starting from 10.7 g of N, N'-carbonyl-imidazole and 10.9 g of 2-amino-7- {3- (dimethylamino) propoxy] -1,8-naphthyridine, the mixture is stirred for 6 hours. keeping at reflux for a long time. The reaction mixture was poured into 300 cm ^{3 of} water and extracted three times with 10 cm ^{3 of} methylene chloride. The organic phases are evaporated to dryness under reduced pressure (4 kPa). 21.4 g of an oily residue are obtained, which is treated with 100 cm <^{3> of} isopropyl oxide with stirring. The resulting crystalline solid, 13.9 g, melting at about 80 ° C, is purified by chromatography on a 34 mm diameter column packed with 140 g of silica, 0.06-0.20 mm. Elution was carried out with a 955 (v / v) mixture of methylene chloride and methanol and a 50 cm ³ fraction was collected. Fractions 41 99 are evaporated to dryness at 40 ° C and 4 kPa under reduced pressure. This gave 10.1 g of a dense oil which was mixed with 110 cm ^{3 of} isopropyl oxide. The resulting solid, 4.3 g, m.p. about 80 ° C was repeatedly purified by flash chromatography at 30 kPa, 130 g 0.04-0.06 mm, 40 mm in diameter. on a silica-filled column. Elution with methylene chloride-methanol 97: 3, by volume mixture of a volume of the collected fractions of 25 cm in ^{the third} 10-50. fractions were evaporated to dryness at 40 ° C and 4 kPa under reduced pressure, and after drying at 40 ° C and 0.07 kPa under reduced pressure, 1 g of N- [7- / 3- (dimethylamino) - m.p. 130 DEG C. to give propoxy-1,8-naphthyridin-2-yl] -4-methoxybenzamide.

2-Amino-7- [3- (dimethylamino) propoxy] -1,8-naphthyridine can be prepared as follows:

89.75 g of 2-amino-7-chloro-1,8-naphthyridine were suspended in 236 cm ^{3 of} 3-dimethylamino-1-propanol and the resulting suspension was preheated to about 30 ° C. Subsequently, 65.8 g of 85% potassium hydroxide solution in pelleted form was added gradually to the suspension. The reaction is exothermic and the temperature rises to 80 ° C by the end of the addition. The mixture was then heated at 90 ° C for a further 30 minutes and then allowed to drop to 60 ° C. The reaction mixture was then poured into 1500 cm ^{3 of} water in the presence of 500 cm ^{3 of} methylene chloride. The decanted organic extract was washed twice with 200 cm <^{3> of} water, dried over magnesium sulfate and then concentrated to dryness at 40 [deg.] C. and 4 kPa under reduced pressure. The resulting oil was crystallized from 300 cm ^{3 of} hexane with stirring. The solid crystals were then separated by filtration, washed with hexane and dried at 20 ° C under reduced pressure (0.07 kPa). 109 g of 2-amino-7- [3- (dimethylamino) propoxy] -1,8-naphthyridine are obtained, m.p. 88 ° C.

Example 3

Proceed as in Example 1, except that 7.1 g of 4-methoxybenzoic acid,

Starting from 7.6 g of Ν, Ν-carbonyldiimidazole and 7.8 g of 2-amino-7- [3- (dimethylamino) -2-methylpropoxy] -1,8-naphthyridine.

The reaction mixture was poured into 500 cm ^{3 of} distilled water and extracted four times with 100 cm ^{3 of} methylene chloride. The organic extracts were dried over magnesium sulfate and evaporated to dryness at 40 ° C under reduced pressure (4 kPa).

The isolated product was dissolved in 50 cm ³ of ethanol was added 9.1 cm ³ of 4N ethereal hydrogen chloride to the solution. The resulting precipitate was collected by filtration, washed with 10 cm ^{3 of} ethanol and dried at 40 ° C under reduced pressure (0.07 kPa).

The product was dissolved in ethanol in 550 cm ³ of boiling. The solution was cooled for 3 hours at 4 ° C, then the solid crystalline material was removed by filtration, washed with 10 cm ^{3 of} ethanol and then dried under reduced pressure (0.07 kPa) and dried at 40 ° C. 4.65 g of N-7- [3- (dimethylamino) -2-methylpropoxy] -1,8-naphthyridyl-2-yl -4-methoxybenzamide hydrochloride are obtained, m.p. 260 ° C. .

2-Amino-7- {3- (dimethylamino) -2-methylpropoxy] -1,8-naphthyridine can be prepared as follows:

A mixture of 21 g of 2-amino-7-chloro-1,8-naphthyridine, 54.8 g of 3-dimethylamino) -2-methylpropanol and 15 g at 120 [deg.] C. is heated for three and a half hours. , Consists of 4 g of 85% potassium hydroxide in pastilles. The reaction mixture was then poured into 500 cm ^{3 of} distilled water and extracted three times with 300 ml of methylene chloride. The organic extracts were washed three times with 200 ml of distilled water, dried over magnesium sulfate and evaporated to dryness at 40 ° C and 4 kPa under reduced pressure.

The product thus obtained is diluted with 50 cm <^{3> of} ethanol and 82.5 ml of 4N hydrochloric acid in ether are added. The resulting precipitate was collected by filtration, washed twice with 50 cm <^{3> of} ethanol and air dried.

The isolated product is dissolved in 200 cm ^{3 of} distilled water and to this solution is added 450 cm @ 3 of 5% aqueous sodium carbonate solution. The mixture was extracted four times with 200 cm <^{3> of} methylene chloride and the extracts were washed six times with 300 cm <^{3> of} distilled water, dried over magnesium sulfate and then evaporated to dryness at 40 [deg.] C. and 4 kPa.

This product is dissolved in 500 cm ³ of boiling isopropyl oxide. The solution was cooled at 4 ° C for 18 hours, the resulting solid crystalline material was removed by filtration, washed twice with 10 cm ^{3 of} isopropyl oxide, then dried at 40 ° C and 0.07 kPa under reduced pressure. This gives 8.5 g of 2-amino-7- [3- (dimethylamino) -2-methylpropoxy] -1,8-naphthyridine, m.p.

Example 4

Proceed as in Example 1, except that 4.1 g of 4-methoxybenzoic acid, 4.3 g of Ν, Ν'-carbonyldiimidazole and 5 g of 2-amino-7- [3- Starting from (diethylamino) propoxy] -1,8-naphthyridine. The reaction mixture was then poured into 500 cm ^{3 of} distilled water and extracted twice with 100 cm ^{3 of} methylene chloride. The organic extract was extracted with 100 cm ^{3 of} methylene chloride. The organic extracts are washed with 100 cm ^{3 of} distilled water, dried over magnesium sulfate and then concentrated to dryness at 40 ° C and 4 kPa under reduced pressure.

The material thus obtained is dissolved in 15 cm ^{3 of} ethanol and 3.9 cm ^{3 of} 4N hydrochloric acid in ether are added. The resulting white precipitate was collected by filtration, washed with 10 cm ^{3 of} ethanol and dried at 40 ° C under reduced pressure (0.07 kPa). This was dissolved in 100 cm ³ of boiling ethanol. After cooling for 3 hours at 4 'Con, the resulting solid crystalline material was collected by filtration, washed with 10 cm ^{3 of} ethanol and dried at 40 ° C under reduced pressure (0.07 kPa). This gives 25 g of N-7- [3- (diethylamino) propoxy] -1,8-naphthyridin-2-yl) -4-methoxybenzamide as a partial hydrate (4.6) at 200 ° C. % water) and then melts at 240 ° C.

2-Amino-7- [3-diethylamino-propoxy] -1,8-naphthyridine can be prepared as follows.

A mixture of 26.9 g of 2-amino-7-chloro-1,8-naphthindine, 78 g of 3- (d-1-dimethylamino) -1-propanol and 19.74 g is maintained at 120 ° C for 3 hours. It is made up of 85% potassium hydroxide, pelleted. The reaction mixture was poured into 500 cm ^{3 of} distilled water and then extracted three times with 50 cm ^{3 of} methylene chloride. The organic extracts were washed with 500 cm ^{3 of} distilled water, dried over magnesium sulfate and evaporated to dryness at 40 ° C and 4 kPa under reduced pressure.

The product obtained is dissolved in 100 cm <^{3> of} ethanol and 10 cm <^{3> of} 3.5N hydrochloric acid in ether are added to the resulting solution. The resulting precipitate was collected by filtration, washed with ethanol ( ² x 50 cm ³ ) and dried at 40 ° C under reduced pressure (0.07 kPa).

This product is dissolved in 100 cm ³ of boiling ethanol. After cooling for 3 hours at 4 ° C, the solid crystalline material was removed by filtration, washed with 10 cm ^{3 of} methanol and dried at 40 ° C under reduced pressure (0.07 kPa). The resulting material is dissolved in 10 cm ^{3 of} distilled water and 55 cm ^{3 of a} 5% sodium carbonate solution are added to the resulting solution. The solution was extracted three times with 60 cm <^{3> of} methylene chloride. The organic extracts were washed five times with 100 cm <^{3> of} water, dried over magnesium sulfate and then evaporated to dryness at 40 [deg.] C. and 4 kPaos. This gives 5 g of 2-amino-7- [3- (diethylamino) propoxy] -1,8-naphthyridine as a brown oil which is used as is in the next step of the synthesis.

Example 5

The procedure described in Example 1, except that 9.9 g of 4-methoxybenzoic acid, 10.5 g of Ν, Ν'-carbonyldiimidazole and 14.2 g of 2-amino-7- [2 - (4-Methyl-1-piperazinyl) ethoxy] -1,8-naphthyridine. The reaction mixture was poured into 600 cm of water and extracted three times with ⁹ 600 cm ³ of methylene chloride. The organic phases are evaporated to dryness under reduced pressure (4 kPa) and the residue is dissolved in 150 cm <^{3> of} ethanol and 30.3 cm <^{3> of} 3.1 N hydrochloric acid in ether are added. The precipitate formed is filtered off, washed with 15 cm < ³ > of ethanol and then dried at 45 [deg.] C. and 0.07 kPa under reduced pressure. The residue obtained is dissolved in 150 cm ^{3 of} distilled water.

The resulting solution was basified to pH 10 with 4N sodium hydroxide solution and the resulting precipitate was extracted with 150 cm ^{3 of} methylene chloride. After decantation, the aqueous phase is re-extracted twice with 150 cm @ ^{3 of} methylene chloride. The organic extracts were washed twice with 100 cm ^{3 of} water, dried over magnesium sulfate and then evaporated to dryness at 70 ° C and 4 kPa under reduced pressure.

The resulting oily residue was dissolved in 50 cm ^{3 of} ethanol. To the resulting solution was added fumaric acid dissolved in 50 cm ^{3 of} ethanol. After cooling for two hours at 4 ° C, the precipitated solid crystalline material was filtered off, washed with ethanol (15 cm ³ ) and dried at 40 ° C under reduced pressure (0.07 kPa). This gives N-7- [2- (4-methyl-1-piperazinyl) ethoxy] -1,8-naphthyridine-241 -4-methoxybenzamide fumarate (10.2 g), m.p. 175 ° C. .

2-Amino-7- [2- (4-methyl-1-piperazinyl) ethoxy] -1,8-naphthyridine can be prepared as follows:

A mixture of 18 g of 2-amino-7, -chloro-1,8-naphthyridine, 2.88 g of 1- (2-hydroxyethyl) 4-methylpiperazine was heated at 105 ° C for six and a half hours. and 7 g of powdered 80% potassium hydroxide. The reaction mixture was then poured into 800 cm ^{3 of} distilled water and extracted three times with 200 cm ^{3 of} methylene chloride. The organic extracts were washed with water, dried over magnesium sulfate and evaporated to dryness at 70 ° C and 4 kPa under reduced pressure.

The oily residue thus obtained is purified by chromatography on a column 32 mm in diameter. The column containing 250 g of neutral alumina as a filler was eluted with methylene chloride and the fractions were collected in 50 cm ^3. 3 -45. fractions were evaporated to dryness at 60 ° C and 4 kPa under reduced pressure. In this way, 10 g of 2-amino-7- [2- (4-methyl-1-piperidinyl) ethoxy] -1,8-naphthyridine were obtained in the form of a dense gum.

1- (2-Hydroxyethyl) 4-methylpiperazine can be prepared by the procedure described by Zotta V. et al., Farmacia, 10, 605 (1962).

Example 6

The procedure is as described in Example I, except that 8 g of 4-methoxybenzoic acid, 85 g of Ν, -'-carbonyldiimidazole and 9.6 g of 2-amino-7- (2- morpholinoethoxy) -1,8-naphthyridine. The product was precipitated with 500 cm ³ of water, and at first, subsequently washed with 500 cm ³ 250 cm ³ of water and dried over magnesium sulfate. The organic extracts were evaporated to dryness at 50 ° C and 4 kPa under reduced pressure.

The resulting oily substance (17.3 g) was subjected to flash chromatography under reduced pressure (30 kPa) on a 40 mm diameter column filled with 173 g of silica having a grain size of 0.04-0.06 mm. Elution was carried out with a 98: 2 mixture of methylene chloride and methanol and 50 ml of the fractions were collected.

48-95. fractions were evaporated at 40 ° C and under reduced pressure (4 kPa), and the resulting 13.4 g was dissolved in 100 cm ^{3 of} ethanol. To the solution is added 9 cm ^{3 of a} 3.8 normal hydrochloric acid solution. The resulting precipitate was filtered and washed three times with 20 cm <^{3> of} diethyl oxide and dried at 50 [deg.] C. under reduced pressure (0.07 kPa). This was dissolved in 250 cm ³ of boiling ethanol. After cooling for two hours at 4 ° C, the solid crystalline material is separated off, washed three times with 20 cm ^{3 of} 1-propanol and dried at 40 ° C under reduced pressure (0.07 kPa). This gave 9 g of N-7- [2-morpholinoethoxy] -1,8-naphthyridin-2-yl -4-methoxybenzamide, m.p. 242 ° C.

2-Amino-7- (2-morpholinoethoxy) -1,8-naphthyridine can be prepared as follows:

16.2 g of 2-amino-7-chloro-1,8-naphthyridine are suspended in 450 cm ^{3 of} chlorobenzene. To this suspension are added 1.47 g of tris (dioxa-3,6-heptyl) amine, 6.75 g of powdered 80% potassium hydroxide and 12 g of morpholinoethanol. The temperature of the mixture was raised to 120 ° C and the mixture was maintained at this temperature for three hours. After cooling, the resulting suspension was separated by filtration. The separated material was washed three times with 50 cm ^{3 of} chlorobenzene and three times with 50 cm ^{3 of} water. The resulting solid was re-dissolved in 400 cm ^{3 of} methylene chloride. Insoluble material in the solution was removed by filtration _b The filtrate was dried over magnesium sulfate and evaporated to dryness at 40 ^e C and 4 kPa under reduced pressure. 235 g of crude product, which melts at 164 ^o C. The crude product is mixed J00 cm ³ of isopropyl oxide, filtered and dried at 30 ^e C and 0.07 kPa reduced pressure. This way

13.9 g of 2-amino-7- (2-morpholinoethoxy) -1,8-naphthyridine are obtained, m.p.

Example 7

Proceed as described in Example 1, except that 21.3 g of 4-methoxybenzoic acid,

22.7 g of Ν, Ν'-carbonyldiimidazole and 30.6 g of 2-amino-7- [2- (N-methyl-N- (tertiary-butoxycarbonyl) amino) -e] Starting from 1,8-naphthyridine. The reaction mixture was poured into 1000 cm ^{3 of} water and extracted twice with 500 cm ^{3 of} methylene chloride. The organic extracts were washed with 500 _{cc of} water, dried over magnesium sulfate and then evaporated to dryness at 50 C and 4 kPa under reduced pressure.

The resulting oily material was purified by chromatography on a 60 mm diameter column packed with silica (400 g, 0.06-020 mm). 5050 eluting with an eluent mixture of ethyl acetate / cyclohexane, and 100 cm ³ was collected from the fractions. 6-20. fractions were evaporated to dryness at 40 ° C and 4 kPa under reduced pressure. This gives 35 g of a dense oily substance which is dissolved in 75 cm ^{3 of} ethanol and added to 4.35 cm ^{3 of} the resulting solution.

3.8N HCl in ether. The resulting precipitate was collected by filtration, washed three times with 20 cm ^{3 of} ethanol and then dried at 40 ° C and 0.07 kPa under reduced pressure. The resulting material was dissolved in acetonitrile in 280 cm ³ of boiling. After cooling for three hours at 40 ° C, the resulting crystalline material is filtered off, washed three times with 20 cm <^{3> of} diethyl oxide, and then dried at 50 [deg.] C. under reduced pressure. 6.5 g of N-7- [2- (N-methyl-N- (tert-butoxycarbonyl) amino) ethoxy] -1,8-naphthyridine-241 4-methoxybenzamide are obtained, m.p. you are on.

2-Amino-7- [2- (N-methyl-N- (tert-butoxycarbonyl) amino) -ethoxy] -1,8-naphthyridine can be prepared as follows:

a mixture of 112 g of 2-amino-7-chloro-1,8-naphthyridine, 1500 cm ^{3 of} toluene, 109.4 g of 2- (N-methyl-N- (tert-butoxy) is stirred at 50 ° C for 1 h. -carbonylamino) -ethanol, 350 g of 50% aqueous sodium bicarbonate solution and 14.2 g of benzyltriethylammonium chloride The resulting insoluble material is separated by filtration and three times with 100 cm ^{3 of} toluene and four times with 100 cm ^{3 of} water. washed.

The organic phase of the filtrate was separated by decantation, washed three times with 300 cm <^{3> of} distilled water, dried over magnesium sulfate and then concentrated to dryness at 60 [deg.] C. and under reduced pressure (4 kPa). The residue was dissolved in acetonitrile to 225 cm ³ of boiling. After cooling for two hours at 4 ° C, the resulting solid crystalline material was collected by filtration, washed three times with 20 cm ^{3 of} acetonitrile and air-dried. 30.6 g of 2-amino-7- [2- (N-methyl-N- (tert-butoxycarbonyl) -anthine) ethoxy] -7-13-naphthyridine are obtained, m.p. melted

2- [N-Methyl-N- (tert-butoxycarbonyl) amino] retanol can be prepared as follows:

Gradually add 70 g of sodium carbonate to a solution of 50 g of 2-methylaminoethanol in 850 cm ^{3 of} water. The temperature gradually increases during the addition by 25 ^? From C to 38'C. To the resulting mixture was added a solution of 155 g of di-tert-butyl dicarbonate in 700 cm ^{3 of} dioxane over 5 minutes. The reaction is slightly exothermic. After stirring for 15 hours at about 20 ° C, the resulting suspension was filtered and washed with 100 cm ^{3 of} water. The filtrate was extracted three times with 500 cm ^{3 of} methylene chloride, and the combined organic extracts were washed with 500 cm ^{3 of} water, dried over magnesium sulfate and evaporated to dryness at 60 ° C under reduced pressure (4 kPa). 114.7 g of 2- [N-methyl-N- (tert-butoxycarbonyl) amino] -ethanol are thus obtained in the form of an oily substance.

Characteristic bands in the infrared spectrum (cm ^-1 ): 3625, 3430, 1675, 1395, 1368, 1160, 1050.

Example 8 cm ³ of trifluoroacetic acid was dissolved 20 g of N- 7- [2- (N-methyl-N- (tert-butoxycarbonyl) amino) ethoxy] -l, 8-naphthyridin-2-yl-4- methoxybenzamide and the resulting solution was stirred at about 20 ° C for 1 hour. The reaction mixture was poured into 100 cm ^{3 of} water and neutralized with 180 cm ^{3 of} 4N sodium carbonate solution. Insoluble material was removed by filtration, washed with water and air dried, and then redissolved in 250 cm ³ of boiling acetonitrile. After cooling for two hours at 4 ° C, the resulting crystalline solid was removed by filtration, washed three times with 20 cm ^{3 of} acetonitrile and dried at 50 ° C under reduced pressure (0.07 kPaos). 8.7 g of N-7- [2-9-methylamino-ethoxy] -1,8-naphthyridin-2-yl-4-methoxybenzamide are thus obtained, m.p. 146 ° C.

Example 9

Proceed as in Example 1, except that 9.3 g of ból, Ν'-carbonyldiimidazole and 9.1 g of 2-amino-7- (dimethyl) are obtained from 9.3 g of 4-methoxybenzoic acid. starting from carbamoylmethoxy) -1,8-naphthyridine. The reaction mixture was poured into 1250 cm ³ of water and the resulting precipitate was collected by filtration, washed with water and dried at 40 ° C under reduced pressure (0.07 kPa). This gave 9.2 g of a solid, m.p. 110 ° C. The filtrate was extracted with methylene chloride (2 x 500 cm ³ ), washed with water and concentrated to dryness at 50 ° C under reduced pressure ( ₇ kPa). This gives 4 g of a gummy material. The two products thus obtained were combined and purified by flash chromatography under reduced pressure (30 kPaos) on a 40 mm diameter column containing silica (0.04-0.06 mm). Elution with methylene chloride-methanol 99: 1 by volume mixture of and 50 cm ³ fractions were collected. 23-120. fractions were evaporated to dryness at 40 [deg.] C. and under reduced pressure (4 kPaos) to give 7.3 g of an amorphous solid. This material was mixed with 150 cm ^{3 of} diethyl ether and the resulting solid was filtered, washed with diethyl ether and air dried. The crystalline solid was then dissolved in 50 cm ^{3 of} 5050 boiling ethanol / water. After cooling for two hours at 4 ° C, the resulting solid was collected by filtration, washed three times with 20 cm ³ of the solvent used for crystallization and dried at 50 ° C under reduced pressure (0.07 kPa). 4.3 g of N- [7- (dimethylcarbamoylmethoxy) -1,8-naphthyridin-2-yl] -4-methoxybenzanide are thus obtained, m.p. 165 ° C.

2-Amino-7- (dimethylcarbamoylmethoxy) -1,8-naphthyridine can be prepared as follows:

7.5 g of powdered 80% potassium hydroxide was gradually added to a suspension preheated to 70 ° C of 12 g of 2-amino-7-chloro-1,8-naphthyridine and 25.7 g of Ν, Ν-dimethyl -Glycolamide. The reaction is exothermic. The temperature is maintained at about 100 ° C during the addition. Once the addition is complete, the mixture is heated at 90 ° C for an additional 1.5 hours. After cooling, the reaction mixture was poured into 200 cm ^{3 of} water and the mixture extracted four times with 200 cm ³ of methylene ldoriddal. The organic extracts are washed with 200 cm ^{3 of} water, dried over magnesium sulfate and evaporated to dryness at 50 ° C and 4 kPa under reduced pressure.

The material thus obtained was mixed with 100 cm ^{3 of} dimethyl ether. The crystallized solid was filtered, washed with diethyl ether and dried at 50 ° C under reduced pressure (0.07 kPa). Exemplary of such a procedure 10.2 g of 2-amine p -7 - {dimethyl carbamoyl-methoxy) -1 $ naphthyridine is obtained, mp 182 ^° F.

Ν, Ν-Dimethylglycolamide can be prepared as described by W. P. Ratchford et al., J. Org. Chem., 15, 317 (1950).

Example 10

The procedure described in Example 1 was followed, except that 21.1 g of 4-methoxybenzoic acid, 22.5 g of Ν, Ν'-carbonyldiimidazole and 22 g of 2-amino-7- [2- ( starting from dimethylamino) ethylthio] -1,8-naphthyridine. The product obtained - after the reaction mixture is treated in such a manner as described in Example 1 and the drying is carried out - is dissolved in 600 cm ³ of dimethylformamide and treated with 52 cm ³ of 3 normal hydrochloric acid in ether. The resulting precipitate was collected by filtration and washed three times with 30 cm <^{3> of} diethyl ether and then dried at 40 [deg.] C. and under reduced pressure (0.07 kPa).

This was dissolved in 750 ^cm3 of boiling methanol. After cooling for 3 hours at 4 ° C, the solid crystalline material is filtered off, washed with 3.0 cm ^{3 of} methanol and dried at 40 ° C under reduced pressure. 23.6 g of N-7- [2- (dimethylamino) ethylthio] -1,8-naphthyridine-2-U-4-methoxybenzamide dihydrochloride are obtained, m.p. while melting.

2-Amino-7- [2- (dimethylamino) ethylthio] -1,8-naphthyridine can be prepared as follows:

For two hours at 90 ° C for ^such a mixture which hydroxide pellets 29.6 g of 2-amino-7-chloro-l, 8-naphthyridine, 48 g of 2- (dimethylamino) -etántiolból, 435 g, 85 It consists of t% potassium hydroxide and 300 cm ^{3 of} dimethyl 81-sulfis. The reaction mixture was then poured into 400 cm ^{3 of} distilled water and extracted six times with 250 cm ^{3 of} methylene chloride. The extracts were washed with 300 cm ^{3 of} distilled water, dried over magnesium sulfate, and then concentrated to dryness at 40 ° C under reduced pressure. The resulting residue is taken up in 100 cm ^{3 of} ethanol and the insoluble material is filtered off, washed twice with 30 cm ^{3 of} ethanol and then dried at 40 ° C and 0.07 kPa under reduced pressure. This gave 22 g of 2-amino-7- [2- (dimethylamino) ethylthio] -1,8-naphthyridine, m.p. 174 ° C.

Example 11

Proceed as in Example 1, except that 5.32 g of 4-methoxybenzoic acid, 5.67 g of Ν, Ν'-carbonyldiimidazole and 9 g of 2-amino-7- [3- (dimethylamino) propylthio] -1,8-naphthyridine. The reaction mixture was poured into 1000 ml of distilled water and extracted three times with 300 cm ³ of methylene chloride. The organic extracts were washed with 200 cm ^{3 of} distilled water, dried over magnesium sulfate and evaporated to dryness at 40 ° C under reduced pressure (4 kPa).

9.32 g of a chestnut-colored residue obtained is dissolved in 50 cm ³ of ethanol was added 4.6 cm ³ of 4.7 normálos ethereal hydrogen chloride to the solution. The resulting precipitate was removed by filtration, washed with 10 cm ³ of diethyl ether and 40 ° C, dried under reduced pressure of 0.07 kPa, and the resulting residue was dissolved in 20O cm ³ of 1-propanol at reflux. After cooling for 15 hours at 4 ° C, the resulting solid crystalline material was collected by filtration, washed twice with 10 cm ^{3 of} 1-propanol and dried at 40 ° C under reduced pressure (0.07 kPa). 7.24 g of N-7- [3- (dimethylamino) propylthio-1,8-naphthyridin-2-yl-4-methoxybenzamide are thus obtained in the form of its hydrochloride salt, m.p. 21 ° C.

2-Amino-7- (3-dimethylanino) -propylthio-1,8-naphthyridine was prepared as follows:

A mixture of 8 g of 2-amino-7-chloro-1,8-naphthyridine, 11.4 g of 3- (dimethylamino) propanethiol, 6.26 g of pastilles is kept at 90 ° C for three and a half hours. It consists of 85% potassium hydroxide and 87 cm ³ dimethylsulfoxide. The reaction mixture was then poured into 1500 cm ^{3 of} water and extracted five times with 400 cm ^{3 of} methylene chloride. The organic extracts were combined and washed with 400 cm ³ of distilled water, dried over magnesium sulfate and 40 ° C, 4 kPa under reduced pressure to dryness. The resulting residue was treated with 100 cm ^{3 of} diethyl ether. The insoluble residue was removed by filtration, washed with diethyl ether (10 cm ³ ) and dried at 40 ° C under reduced pressure (0.07 kPa). This gives 9 g of 2-amino-7- [3- (dimethylamino) -propylthio] -1,8-naphthyridine, m.p. 164 ° C.

Example 12

The procedure described in Example 1 was followed except that 5.5 g of benzoic acid, 8.1 g of N, N'-carbonyldimethimidazole and 11.6 g of 2-amino-7- [2- ( starting from dimethylaminophenyl ethoxyl-1,8-naphthyridine. This mixture was refluxed for 5 hours, then poured into 1500 cm ^{3 of} water and extracted twice with 1000 cm ^{3 of} ethyl acetate. The organic phases are evaporated to dryness under reduced pressure (4 kPa) and the resulting 9.2 g of an oily residue is dissolved in 25 cm ^{3 of} boiling ethyl acetate. After cooling for two hours at 4 ° C, the solid crystalline material was collected by filtration, washed with 3 cm ^{3 of} ethyl acetate and dried at 40 ° C under reduced pressure (0.07 kPa). This gave 45 g of N-7- [2- (dimethylamino) ethoxy] -1,8-naphthyridin-2-ylbenzamide, m.p. 109 ° C.

Example 13

The procedure described in Example 1 was followed, except that 11.3 g of 2,6-difluorobenzoic acid, 12.9 g of Ν, Ν'-carbonyldiimidazole and 11.8 g of 2-amino - [ Starting from 3-dimethylamino-propoxy-1,8-naphthyridine. The product is obtained by precipitation with water and, after drying, dissolved in 450 cm ^{3 of} acetone while boiling. After cooling at 4 ° C for 3 hours, the solid crystalline product is isolated by filtration, washed with 10 cm ^{3 of} acetone and dried at 40 ° C under 0.07 kPa. 72 g of N-7- [3- (dimethylamino) propoxy] -1,8-naphthyridin-2-yl-2,6-difluorobenzamide are obtained, m.p. 190 ° C.

Example 14

Proceed as in Example 1, except that 7 g of 4- [N- (ethyl) -trifluoroacetamido-benzoic acid, 4.2 g of Ν, Ν'-carbonyldiimidazole and 3.5 g of Starting from 2-amino-7-methoxy-1,8-naphthyridine. The reaction mixture was then poured into 1000 cm ^{3 of} water and extracted twice with 200 cm ^{3 of} methylene chloride. The organic extracts were dried over magnesium sulfate and evaporated to dryness at 40 ° C under reduced pressure (4 kPa).

The resulting material is dissolved with five refluxoltatás 20 cm ³ of methanol and treated with 150 cm ³ of isopropyl oxide to the solution. The precipitate is collected washed twice with 10 cm ^ ³ of isopropyl oxide by filtration and dried at 40 C for ^Ti, 0.07 kPa reduced pressure. 5.1 g of N- (7-methoxy-1,8-naphthyridin-2-yl) -4- [N '- (ethyl) -trifluoroacetamido] -benzamide are obtained, m.p. 150 ° C.

Elewe (5 g of N- (7-methoxy-1,8-naphthyridin-2-f) 4-N '- (ethyl) trifluoroacetamido] -benzamide) was heated at 80 ° C for 1 minute. ³ 7% aqueous potassium carbonate solution and 25 cm ³ of methanol D-. The resulting precipitate was collected by filtration, washed four times with 20 cm ^{3 of} distilled water and dried at 40 ° C under reduced pressure of 0.07 kPa.

The product was dissolved in 50 ^cm3 of boiling methanol. For two hours at 20 ° C tarfiuk the solution, and the precipitated crystals were removed by filtration, washed with 10 cm ³ of methanol and dried at 40 ^e C and reduced pressure. Illustrative 22 g of N- (7-methoxy-l, 8-naphthyridin-2-yl) -4- (ethylamino) -jjenzamidot obtained, mp 134 C, ^e, partly exist as its hydrate (22% water) and 174 ^e C.

4- {N (ethyl) -trifluoroacetamido] -benzoic acid can be prepared as follows:

After stirring at 25 ^e C .9 mixture was stirred for five hours, which consists of 18 g of 4-furan tetrahydrofuran <ethylamino) -benzoic acid, 20.7 cm trifluoro-acetic anhydride and 100 cm from ^{the third} The mixture was then poured into 200 cm ^{3 of} water and extracted twice with 200 cm ^{3 of} methylene chloride. The organic extracts were washed with distilled water (220 cm ³ ), dried over magnesium sulfate and then concentrated to dryness at 40 ° C and 4 kPa under reduced pressure. The product obtained is purified by chromatography on a 40 mm diameter column filled with 320 g of 0.04-0.06 mm silica. Elution was carried out with a 98% v / v mixture of methylene chloride and methanol. We collect 20 cm from your fraction. 2-21. fractions were dried to dryness at 40 ° C and 4 kPa under reduced pressure. 7 g of 4-N- (ethyltrifluoroacetamido) benzoic acid are obtained, m.p. 132 ° C.

4- (Ethylamino) -benzoic acid can be prepared as follows:.

After stirring for 1 hour at 25 ° C, a mixture of 30 g of 4-aminobenzoic acid, 32.3 g of sodium borohydride and 550 µl of ³ acetic acid was stirred. The reaction mixture was evaporated to dryness and 70 ^e C 4kPaos reduced pressure thereafter. The resulting residue was treated with 2000 cm ^{3 of} distilled water and the resulting precipitate was collected by filtration, washed with 20 cm ^{3 of} distilled water and air dried. This was dissolved in 250 cm ³ of boiling acetonitrile. The solution was cooled to 25 ° C and held at this temperature for two hours. The solid crystalline material was collected by filtration, washed with 10 cm ^{3 of} acetonitrile and dried at 40 ° C and 0.07 kPa under reduced pressure. 18 g of 4-ethylamino-benzoic acid are thus obtained, m.p. 174 ° C.

Example 16

The procedure described in Example 1 was repeated except that 5.75 g of cyclopropanecarboxylic acid, 10.9 g of Ν, Ν'-carbonyldiimidazole and 12.3 g of 2-amino-7- [3- (dimethyl- amino) -propoxy] -1,8-naphthyridine. The reaction mixture was poured into 800 cm ^{3 of} water and extracted three times with 200 cm ^{3 of} methylene chloride. The organic extracts were combined and washed three times with 100 cm <^{3> of} water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (4 kPa). The resulting oily material was dissolved in 40 cm ^{3 of} ethanol at 40 ° C, then kept in the dark and 150 cm ^{3 of} distilled water was added to the filtrate. After cooling for 4 hours at 4 ° C, the resulting solid was collected by filtration, washed with 20 cm ^{3 of} a 1: 3 by volume mixture of ethanol and water and at 20 ° C; It was dried under reduced pressure (0.07 kPa).

The resulting 12 g of solid was dissolved in 20 cm ³ of ethanol. To this solution was added 50 cm ³ dissolved in ethanol and 4.4 g of fumaric acid. After 2 hours at 4 ° C, the solid crystalline material was removed by filtration, washed with 20 cm ^{3 of} ethanol and dried at 40 ° C under reduced pressure (0.07 kPa). 11 g of N- {7- [3- (dimethylamino) propoxy] -1,8-naphthyridine -2411-cyclopropanecarboxamide fumarate were obtained, m.p. 210 ° C.

Example 15

The procedure is as described in Example 1, except that 7.3 g of 4- (ethoxycarbonylamino) benzoic acid, 5.6 g of N, N-carbonyldiimidazole and 4.7 g of 2 starting from amino-7-methoxy-1,8-naphthyridine. The reaction mixture was then poured into water and the resulting white precipitate was collected by filtration, washed with 10 cm &lt; 3 &gt; water and orally for 18 hours.

g of 194 ^o C. There was thus obtained residue which was dissolved in 150 cm ³ of boiling acetonitrile. The solution was cooled to 25 ° C and held at this temperature for 2 hours. The solid crystalline material was collected by filtration, washed twice with 10 cm ^{3 of} acetonitrile and dried at 40 ° C under reduced pressure. 65 g of N- (7-methoxy-1,8-naphthyridin-2-yl) -4-ethoxycarbonylamino-benzamide are obtained, m.p. 200 ° C.

4- (ethoxycarbonylamino) benzoic acid can be prepared as follows:

After stirring for 5 minutes at 5 ° C, a mixture of 10 g of 4-aminobenzoic acid, 365 cm ^{3 of} normal aqueous sodium bicarbonate solution and 7 cm ^{3 of} ethyl chloroformate was stirred. Then 150 cm ^{3 of} 25N hydrochloric acid are added to the reaction mixture. The precipitate was separated by filtration and washed three times with 200 cm ³ of water, then dried 40 ^e C 0.07 kPa reduced pressure. In this way 133 8 4- (ethoxycarbonyl-amino) benzoic acid was prepared, which melts at 207 ^e C.

EXAMPLE 17 cm ³ of methylene chloride were dissolved in 6 g of N-7- [2- (dimethylamino) ethylthio] -l, 8-naphthyridine-24l _e 4-methoxy-benzamide, then this page 0 C- 3.6 g of 3-doroperbenzoic acid are added. After stirring for 2 hours at 0 ° C, the reaction mixture was poured into 200 cm ^{3 of} 5% sodium carbonate solution and extracted four times with 100 cm ^{3 of} methylene chloride. The organic extracts were washed with 100 cm ^{3 of} distilled water, dried over magnesium sulfate and concentrated at 40 ° C under reduced pressure (4 kPa).

The material was separated by flash chromatography on a reduced pressure silica gel column (50 g, 0.04-0.06 mm) at 30 kPa. Gel using methylene chloride and methanol as eluent 95 5, and 50 cm ³ fractions were collected. 3-13. fractions were evaporated to dryness at 0 ° C and under reduced pressure of 4 kPa. This gave 23 g of a solid, m.p. 140 ° C. This product was dissolved in 30 cm ³ of acetonitrile to reflux and heated for one hour at 5 ° C. Separating the crystals filtered, washed twice with 10 cm ³ of diethyl ether and 40 ^e C, 0.07 kPa vacuo ltjuk mouth. In this way, 2/2 g of N- [7- [2- (dimethylamino) ethyl] sulfinyl] * 1,8-naphthyriglyin-2411-4-methoxybenzanide, m.p. 158 DEG C., are obtained.

-101

196 070

Example 18 12 g of N- (7-methyl-1-naphthyridin-2-yl) 4-methoxybenzamide is suspended in cm ^{3 of} anhydrous diethylformamide and 28 g of tert-butoxybis (dimethylamino) are added to this suspension. methane. The resulting mixture was stirred at 130 ° C for three hours. The resulting solution was poured into 100 cm ^{3 of} water and then extracted with 200 cm ^{3 of} methylene chloride. The organic extracts were washed with water (2 x 100 cm ³ ), dried over magnesium sulfate and then evaporated to dryness at 50 ° C and reduced pressure of 10 psi. The resulting amorphous residue was dissolved in 100 cm ³ of carbon tetrachloride. Slow addition of 150 cm ^{3 of} isopropyl oxide precipitates a solid crystalline material which is filtered off, washed with 30 cm ^{3 of} isopropyl oxide and air dried. 92 g of base are obtained, m.p. 110 ° C. This material was dissolved in 150 cm <^{3> of} ethanol and 20 cm <^{3> of} 4.7 N hydrochloric acid in diethyl ether were added. The resulting precipitate was separated was washed three times with 30 cm ³ of diethyl ether and then dried at 25 ^e C, 4 kPaos filtration under reduced pressure. The crude hydrochloride salt obtained is purified by recrystallization from 160 cm ^{3 of} ethanol. 6 g of N-7- [2- (dimethylamino) vinyl] -1,8-naphthyridin-2-yl 4-methoxybenzamide are thus obtained in the form of the hydrochloride salt, m.p. 240 ° C.

N- (7-Methyl-1,8-naphthyridin-2-yl) 4-methoxybenzamide is prepared as previously described in U.S. Pat. No. 2,567,887. Fraction Patent Application Ser.

Pharmaceutical compositions prepared from the compounds of the present invention are either pure compounds of Formula I or are compatible with pharmaceutically acceptable excipients, diluents; and / or coating agents, these agents are present in these formulations. The pharmaceutical compositions so prepared can be administered orally, intestine, not via the intestine and transdermally.

Solid compositions suitable for oral administration may be in the form of tablets, pills, powders (usually in gelatin capsules) or granules. In these formulations, the active ingredients of the present invention are found in combination with a variety of inert diluents, such as sucrose, lactose or amidone.

Pharmaceutically acceptable emulsions, solutions, suspensions, syrups, lotions containing inert diluents such as water or paraffin oil may be used as liquid formulations for oral administration. These compositions may also contain auxiliary substances other than diluents, for example a wetting agent, sweetening agent or flavoring agent.

Formulations that are not administered by the enteric route may include aqueous or non-aqueous sterile solutions, suspensions, or emulsions. Propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters, such as ethyl oleate, may be used as solvents or vehicles. These formulations may also contain other excipients, in particular wetting agents, emulsifying agents and dispersing agents. Sterilization may be accomplished in a number of ways, for example by the use of a bacteriological filter, by the addition of sterilizing agents to the formulations, by irradiation or by heating. Heat can also make solid sterile formulations that can be dissolved in a sterile solvent or other injectable sterile medium at the time of use.

Formulations for parenteral administration may be in the form of suppositories which may contain excipients such as cocoa butter or wax used in suppositories, through the active ingredient.

Formulations for transdermal administration include creams, ointments, lotions, and be20 rubbing ointments, wherein the active ingredient is combined with a liquid or paste binder, preferably a vehicle that favors transdermal migration.

Formulations of the active ingredient prepared by the process of the present invention are particularly useful in human medicine because of their anti-anxiety, hypnotic, antispasmodic, antiepileptic and muscle relaxant properties.

The doses used in human medicine depend on the experimentally determined effect and the duration of fc treatment. Generally, amounts of between 10 mg and 500 mg are administered orally daily to an adult.

Generally, the dosage will be determined by the physician, who will determine the appropriate dosage, taking into account the age, weight and other relevant considerations of the subject being treated.

The following examples illustrate compositions which may be prepared from the active compounds of the present invention. These examples are not limiting.

Example "A"

Ordinarily tablets are prepared for administration of 10 mg of active ingredient. The composition of these tablets is as follows:

- N-7- [3-dimethylamino) -propoxy] -1,8-naphthyridin-2-yl 4-methoxy-45-benzamide 0.010 g

0200 g at the time

- 0.036 g of precipitated silica

Magnesium stearate 0.004 g Example B

-n In the usual manner, tablets are prepared for administration of 10 mg of active ingredient. The composition of these tablets is as follows:

N-7- [2- (dimethylamino) ethylthio] -1,8-naphthyridin-2-yl 4-methoxybenzamide at 0.013 g / g. 0200g

- 0.036 g of precipitated silica

Magnesium stearate 0.004 g

Claims (1)

PATENT CLAIMS 60 1. Process 1 is a new substituted compound of formula (1) -111 196.070 for the preparation of amides and acid addition salts of the formula R 3 is C 3-6 cycloalkyl, phenyl, one or two fluorine atoms, the 3- or 4-position being a C 1-4 alkoxy group, or in the 44-position a C 1-4 alkylamino group or a (C 1-4 alkyl) - represents a phenyl group substituted by an oxycarbonylamino group, and There are seven 1,8-naphthyridyl-241 groups substituted at the 7-position by a C 1-4 alkyloxy group, a C 1-4 aldlthio group or a C 1-4 alkylsulfonyl group, which are substituted with N- (C 1-4 alkyl) -N- (C 2-5 alkyloxycarbonyl) amino, di (C 1-4 alkyl) carbamoyl C 1-4 alkylamino, or a di (C 1 -C 4 alkyl) amino group to which they are bonded to form a 6-membered heterocyclic ring optionally substituted with a C 1 -C 4 alkyl group and optionally substituted with another nitrogen or oxygen heteroatom, or at the 7-position substituted with di (C 1 -C 4) alkylamino-vinyl, or R 4 is (C 1 -C 4 alkylamino) phenyl or 4- (C 2 -C 5 alkoxycarbonylamino) phenyl; and There are seven 1,8-naphthyridin-2-yl groups substituted at the 7-position by a C 1-4 alkyloxy group, characterized in that (a) for the preparation of compounds of formula (0) wherein Sev is other than 7- [di (C 1 -C 4 alkyl) -aminovinyl] -1,8-naphthyridin-2-yl, a compound of formula (11) acid - R as defined above - or a reactive derivative thereof with an amine of the general formula (Π1) - Sev is as defined above - and then removing any protecting group (s) present, if desired, to form compounds of formula (I) wherein: Seven are 7- (alkylsulfinyl) -1,8-naphthyridine-241 groups which are N-alkyl-N- (alkyloxycarbonyl) amino or dialkylcarbamoyl or alkylamino-. or a dialkylamino group in which the alkyl moieties of the η nitrogen atom to which they are attached may form a 6-membered heterocyclic ring optionally containing a further heteroatom containing nitrogen or oxygen and optionally substituted with an alkyl group may be a compound of formula (1) obtained wherein R 15 is as defined above and Seven 7- (steady-thio) -1,8-naphthyridin-2 41 is substituted with one of the above substituents and the optional secondary amino groups of which may be protected, is oxidized and then optionally removing any protecting groups present, or B) for the preparation of compounds of the formula I in which there are seven 7- (dialkylamino-vinyl) -1,8-naphthyridine-241- groups, an amine of the formula - R 1 and R ₂ 1-4 R ₃ and R ₄ independently represent C 1-4 alkyloxy or di (C 1 -C 4 alkyl) amino - reacted with a compound of formula (V) - R is as defined above - and, if desired, converting the compound of formula (0) obtained by any process into its acid addition salt. A process for the preparation of a pharmaceutical composition comprising the compound of formula (0) or a pharmaceutically acceptable acid addition salt thereof, as defined in claim 1, wherein R and Sev are as defined above, wherein the active ingredient is in pharmaceutical technology. 35 by known methods.